1,720,969 research outputs found
A beta-induced pathology and neuron loss in the cholinergic system of the APP/PS1ki mouse model of Alzheimer's disease
No full textIntracellular A beta triggers neuron loss in the cholinergic system of the APP/PS1KI mouse model of Alzheimer's disease
No full textLoss of cholinergic neurons in the Nucleus Basalis of Meynert in Alzheimer's disease (AD) patients was one of the first discoveries of neuron loss in AD. Despite an intense focus on the cholinergic system in AD, the reason for this cholinergic neuron loss is yet unknown. In the present study we examined A beta-induced pathology and neuron loss in the cholinergic system of the bigenic APP/PS1KI mouse model. Expression of the APP transgene was found in ChAT-positive neurons of motor nuclei accompanied by robust intracellular A beta accumulation, whereas no APP expressing neurons and thus no intracellular A beta accumulation were found in neither the forebrain or pons complexes, nor in the caudate putamen. This expression pattern was used as a model system to study the effect of intra- and extracellular A beta accumulation on neuron loss in the cholinergic system. Stereological quantification revealed a loss of ChAT-positive neurons in APP/PS1KI mice only in the motor nuclei Mo5 and 7N accumulating intracellular A beta. This study supports the hypothesis of intracellular A beta accumulation as an early pathological alteration contributing to cell death in AD. (C) 2008 Elsevier Inc. All rights reserved
Increasing Abeta peptide levels aggravate axonal degeneration in an Alzheimer mouse model
No full textFormic acid is essential for immunohistochemical detection of aggregated intraneuronal A beta peptides in mouse models of Alzheimer's disease
No full textThe staining protocols so far applied to study intracellular A beta accumulation in human tissue have been inconsistent with varying use of heat and formic acid (FA) for antigen retrieval. Microwave heat treatment has been reported to enhance the staining of intraneuronal A beta as compared to no or enzymatic pretreatment. FA is widely used to increase the staining of plaque pathology in AD, yet the effect of FA on intraneuronal A staining has been reported to be low and similar to the effect of heat or even to counteract the enhancing effect of heat pretreatment on intraneuronal A beta immunohistochemical detection. To overcome these inconsistencies, there is a need for optimization of the staining protocol for intraneuronal. A beta detection and more knowledge is required concerning the effects of the different antigen retrieval methods. in the present work, we optimized the staining protocol for intraneuronal A beta in paraffin-embedded sections in relation to heat and FA using four different mouse models known to accumulate intraneuronal A beta peptides. It was found that FA is essential for the staining of highly aggregated intraneuronal A beta peptides in AD transgenic mouse tissue. (C) 2009 Elsevier B.V. All rights reserve
Increasing Abeta peptide levels aggravate axonal degeneration in an Alzheimer mouse model
No full textALPHA 7 NICOTINIC ACETYLCHOLINE RECEPTOR ACTIVATION PREVENTS SCHIZOPHRENIA RELEVANT BEHAVIORAL AND MOLECULAR CHANGES INDUCED BY REPEATED PCP TREATMENT IN MICE
No full textALPHA 7 NICOTINIC ACETYLCHOLINE RECEPTOR ACTIVATION PREVENTS SCHIZOPHRENIA RELEVANT BEHAVIORAL AND MOLECULAR CHANGES INDUCED BY REPEATED PCP TREATMENT IN MICE
No full textEnvironmental enrichment fails to rescue working memory deficits, neuron loss, and neurogenesis in APP/PS1KI mice
No full textEnvironmental enrichment has been used in a variety of transgenic mouse models of Alzheimer's disease (AD), however, with conflicting results. Here we studied the influence of environmental enrichment in a severely affected AD mouse model, showing a multiplicity of pathological alterations including hippocampal neuron loss. APP/PS1KI and wild type (WT) control mice were housed under standard conditions or in enriched cages equipped with various objects and running wheels. Amyloid plaque load, motor and working memory performance, axonopathy, as well as CA1 neuron number and hippocampal neurogenesis were assessed. Although a partial improvement in motor performance was observed, 4 months of enriched housing showed no beneficial effects in terms of working memory, A beta plaque pathology, or neuron loss in APP/PS1KI mice. In addition, no changes in hippocampal neurogenesis and even an aggravation of the axonal phenotype were detected with a tendency toward a premature death. The APP/PS1KI model represents a model for mild to severe AD showing early behavioral deficits starting at 2 months of age with fast deterioration. Therefore our data might suggest that physical activity and enriched environment might be more beneficial in patients with mild cognitive impairment than in patients with incipient AD. (C) 2012 Elsevier Inc. All rights reserved
alpha(7) Nicotinic acetylcholine receptor activation prevents behavioral and molecular changes induced by repeated phencyclidine treatment
No full textUdgivelsesdato: 2009 May-JunThe core features of schizophrenia include deficits in cognitive processes, such as attention and working memory, subserved by the prefrontal cortex (PFC). These deficits are believed to involve deficient neurotransmission through NMDA receptors, particularly on parvalbumin-containing interneurons, and administration of the NMDA-antagonist phencyclidine (PCP) in rodents is a well validated model of such cognitive deficits. Here we show that repeated PCP treatment (10 mg/kg/day for 10 days) decreased the expression of parvalbumin and synaptophysin mRNA in the mouse PFC, which corresponds to changes seen in patients with schizophrenia. In addition, PCP increased the basal mRNA expression in the PFC of the activity-regulated cytoskeleton-associated protein (Arc), a molecule involved in synaptic plasticity. These molecular changes produced by PCP were accompanied by a behavioral impairment as determined in a modified Y-maze test. Polymorphisms in the alpha(7) nicotinic acetylcholine receptor (nAChR) gene have been linked to schizophrenia. Here we demonstrate that acute administration of the selective alpha(7) nAChR partial agonist SSR180711 dose-dependently reversed the behavioral impairment induced by PCP. Importantly, repeated co-administration of SSR180711 (3 mg/kg) with PCP prevented both the changes in parvalbumin, synaptophysin, and Arc mRNA expression in the PFC, and the behavioral impairment induced by PCP. These results are the first to demonstrate prevention of the deleterious effects induced by repeated PCP treatment. The behavioral and molecular effects of alpha(7) nAChR agonism in this model, particularly the prevention of a decline in parvalbumin mRNA expression, suggest an involvement of the alpha(7) nAChR not only in the symptomatic relief, but also the pathophysiology, of schizophrenia
Transient intraneuronal Aβ rather than extracellular plaque pathology correlates with neuron loss in the frontal cortex of APP/PS1KI mice
No full textThe accumulation of beta-amyloid (A beta) plaques and neurofibrillary tangles consisting of hyperphosphorylated tau protein are pathological features of Alzheimer's disease (AD) commonly modeled in mice using known human familial mutations; however, the loss of neurons also found to occur in AD is rarely observed in such models. The mechanism of neuron degeneration remains unclear but is of great interest as it is very likely an important factor for the onset of adverse memory deficits occurring in individuals with AD. The role of A beta in the neuronal degeneration is a matter of controversial debates. In the present study we investigated the impact of extracellular plaque A beta versus intraneuronal A beta on neuronal cell death. The thalamus and the frontal cortex of the APP/PS1KI mouse model were chosen for stereological quantification representing regions with plaques only (thalamus) or plaques as well as intraneuronal A beta (frontal cortex). A loss of neurons was found in the frontal cortex at the age of 6 months coinciding with the decrease of intraneuronal immunoreactivity, suggesting that the neurons with early intraneuronal A beta accumulation were lost. Strikingly, no neuron loss was observed in the thalamus despite the development of abundant plaque pathology with levels comparable to the frontal cortex. This study suggests that plaques have no effect on neuron death whereas accumulation of intraneuronal A beta may be an early transient pathological event leading to neuron loss in AD
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